Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Ertugliflozin and sitagliptin
The safety of concomitantly administered ertugliflozin and sitagliptin has been evaluated in 990 patients with type 2 diabetes mellitus treated for 26 weeks in three studies; a factorial study of ertugliflozin 5 mg or 15 mg in combination with sitagliptin 100 mg once daily compared to the individual components, a placebo-controlled study of ertugliflozin 5 mg or 15 mg as add-on therapy to sitagliptin 100 mg and metformin once daily, and a placebo-controlled study of initial therapy with ertugliflozin 5 mg or 15 mg once daily in combination with sitagliptin 100 mg once daily (see section 5.1). The incidence and type of adverse reactions in these three studies were similar to the adverse reactions seen with ertugliflozin and are described below in Table 1. There were no additional adverse reactions identified in these three trials that included sitagliptin relative to the three placebo- controlled studies with ertugliflozin (see below).

Ertugliflozin
The safety and tolerability of ertugliflozin were assessed in 7 placebo- or active comparator-controlled studies with a total of 3,409 patients with type 2 diabetes mellitus treated with ertugliflozin 5 mg or 15 mg. In addition, the safety and tolerability of ertugliflozin in patients with type 2 diabetes and established atherosclerotic cardiovascular disease were assessed in VERTIS CV (see section 5.1) with a total of 5,493 patients treated with ertugliflozin 5 mg or 15 mg and a mean duration of exposure of 2.9 years.

Pool of placebo-controlled trials
The primary assessment of safety was conducted in a pool of three 26-week, placebo-controlled trials.
Ertugliflozin was used as monotherapy in one trial and as add-on therapy in two trials (see section 5.1). These data reflect exposure of 1,029 patients to ertugliflozin with a mean exposure duration of approximately 25 weeks. Patients received ertugliflozin 5 mg (N=519), ertugliflozin 15 mg (N=510), or placebo (N=515) once daily.

The most commonly reported adverse reactions across the clinical program were vulvovaginal mycotic infection and other female genital mycotic infections. Serious diabetic ketoacidosis occurred rarely.
See “Description of selected adverse reactions” for frequencies and see section 4.4.

Sitagliptin
Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported.
Hypoglycaemia has been reported in combination with sulphonylurea (4.7%-13.8%) and insulin (9.6%) (see section 4.4).

Tabulated list of adverse reactions
Adverse reactions listed below are classified according to frequency and system organ class (SOC).
Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).


Table 1: Adverse reactions from placebo- and active comparator-controlled clinical trials and post-marketing experience

System Organ Class                                Adverse Reaction
Frequency

Infections and infestations
Very common                                       Vulvovaginal mycotic infection and other female genital mycotic infections*,†,1
Urinary tract infections†,1

Common                                            Balanitis candida and other male genital mycotic infections*,†,1

Not known                                         Necrotising fasciitis of the perineum (Fournier’s gangrene)* Blood and lymphatic system disorders

Rare                                              Thrombocytopenia2

Immune system disorders
Not known                                         Hypersensitivity reactions including anaphylactic ,a,2 responses*
Metabolism and nutrition disorders
Common                                            Hypoglycaemia*,†,1,2 
Rare                                              Diabetic ketoacidosis*,†,1 


Nervous system disorders

Common                                            Headache2
Uncommon                                          Dizziness2
Respiratory, thoracic and mediastinal disorders

Not known                                         Interstitial lung diseasea,2 
Gastrointestinal disorders

Uncommon                                          Constipation2
Not known                                                            a,2 Vomiting
Not known                                                                            a,*,b,2 Acute pancreatitis
Not known
Fatal and non-fatal haemorrhagic and necrotising
*,a,2 pancreatitis
Skin and subcutaneous tissue disorders

Uncommon                                          Pruritusa,2
Not known                                                                       ,2 Angioedemaa,*
Not known                                                       ,2
Rash a,
*
Not known                                                              ,2 Urticariaa,*
Not known
,2
Cutaneous vasculitisa,*
Not known                                         Exfoliative skin conditions including Stevens-Johnson ,2 syndromea,*
Not known                                         Bullous pemphigoida,*,2 Musculoskeletal and connective tissue disorders

Not known                                         Arthralgiaa,2
Not known                                         Myalgiaa,2
Not known                                         Back paina,2
Not known                                         Arthropathya,2
Vascular disorders
Common                                            Volume depletion*,†,1 

Renal and urinary disorders

Common                                                  Increased urination‡,1 Uncommon                                                Dysuria1, Blood creatinine increased/Glomerular filtration rate decreased†,1
Not known                                               Impaired renal functiona,2 Not known                                               Acute renal failurea,2 

Reproductive system and breast disorders
Common                                                  Vulvovaginal pruritus1 
General disorders and administration site conditions

Common                                                  Thirst§,1
Investigations

Common                                                  Serum lipids changed¶,1, Haemoglobin increased**,1, BUN increased¶¶,1
1
Adverse reaction with ertugliflozin.
2
Adverse reaction with sitagliptin.
* See section 4.4.
†
See subsections below for additional information.
‡ Includes: pollakiuria, micturition urgency, polyuria, urine output increased, and nocturia.
§
Includes: thirst and polydipsia.
¶
Mean percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were LDL-C 5.8% and 8.4% versus 3.2%; total cholesterol 2.8% and 5.7% versus 1.1%; however, HDL-C 6.2% and 7.6% versus 1.9%.
Median percent changes from baseline for ertugliflozin 5 mg and 15 mg versus placebo, respectively, were triglycerides -3.9% and -1.7% versus 4.5%.
**
The proportion of subjects having at least 1 increase in haemoglobin > 2.0 g/dL was higher in the ertugliflozin 5 mg and 15 mg groups (4.7% and 4.1%, respectively) compared to the placebo group (0.6%).
¶¶
The proportion of subjects having any occurrence of BUN values ≥50% increase and value >ULN was numerically higher in the ertugliflozin 5 mg group and higher in the 15 mg group (7.9% and 9.8%, respectively) relative to the placebo group (5.1%).
a
Adverse reactions were identified through post-marketing surveillance.
b
See Sitagliptin cardiovascular outcomes study (TECOS) below.


Description of selected adverse reactions
Volume depletion (ertugliflozin)
Ertugliflozin causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse reactions related to volume depletion. In the pool of placebo-controlled studies, the incidence of adverse events related to volume depletion (dehydration, dizziness postural, presyncope, syncope, hypotension and orthostatic hypotension) was low (< 2%) and not notably different across the ertugliflozin and placebo groups. In the subgroup analyses in the broader pool of Phase 3 studies, subjects with eGFR < 60 mL/min/1.73 m2,            subjects ≥ 65 years of age and subjects on diuretics had a higher incidence of volume depletion in the ertugliflozin groups relative to the comparator group (see sections 4.2 and 4.4). In subjects with eGFR < 60 mL/min/1.73 m2, the incidence was 5.1%, 2.6% and 0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and the comparator group and for subjects with eGFR 45 to < 60 mL/min/1.73 m2, the incidence was 6.4%, 3.7% and 0% respectively.

Hypoglycaemia (ertugliflozin)
In the pool of placebo-controlled studies, the incidence of documented hypoglycaemia was increased for ertugliflozin 5 mg and 15 mg (5.0% and 4.5%) compared to placebo (2.9%). In this population, the incidence of severe hypoglycaemia was 0.4% in each group. When ertugliflozin was used as monotherapy, the incidence of hypoglycaemic events in the ertugliflozin groups was 2.6% in both groups and 0.7% in the placebo group. When used as add-on to metformin, the incidence of hypoglycaemic events was 7.2% in the ertugliflozin 5 mg group, 7.8% in the ertugliflozin 15 mg group and 4.3% in the placebo group.

When ertugliflozin was added to metformin and compared to sulphonylurea, the incidence of hypoglycaemia was higher for the sulphonylurea (27%) compared to ertugliflozin (5.6% and 8.2% for ertugliflozin 5 mg and 15 mg, respectively).

In the VERTIS CV sub-studies, when ertugliflozin was added to insulin with or without metformin, the incidences of documented hypoglycaemia were 39.4%, 38.9% and 37.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. When ertugliflozin was added to a sulphonylurea, the incidences of hypoglycaemia were 7.3%, 9.3% and 4.2% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. When ertugliflozin was added to metformin and a sulphonylurea, the incidences of hypoglycaemia were 20.0%, 26.5% and 14.5% for ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively.

In patients with moderate renal impairment taking insulins, sulphonylurea, or meglitinides as background medication, documented hypoglycaemia was 36%, 27% and 36% for ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively (see sections 4.2, 4.4, and 4.5).

Diabetic ketoacidosis (ertugliflozin)
In VERTIS CV, ketoacidosis was identified in 19 (0.3%) ertugliflozin-treated patients and in 2 (0.1%) placebo-treated patients. Across 7 other Phase 3 clinical trials in the ertugliflozin development program, ketoacidosis was identified in 3 (0.1%) ertugliflozin-treated patients and 0.0% of comparator-treated patients (see section 4.4).


Blood creatinine increased/Glomerular filtration rate decreased and renal-related events (ertugliflozin)
Initial increases in mean creatinine and decreases in mean eGFR in patients treated with ertugliflozin were generally transient during continuous treatment. Patients with moderate renal impairment at baseline had larger mean changes that did not return to baseline at Week 26; these changes reversed after treatment discontinuation.

Renal-related adverse reactions (e.g., acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with ertugliflozin, particularly in patients with moderate renal impairment where the incidence of renal-related adverse reactions was 2.5%, 1.3%, and 0.6% in patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively.

Genital mycotic infections (ertugliflozin)
In the pool of three placebo-controlled clinical trials, female genital mycotic infections (e.g., genital candidiasis, genital infection fungal, vaginal infection, vulvitis, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis) occurred in 9.1%, 12%, and 3.0% of females treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. In females, discontinuation due to genital mycotic infections occurred in 0.6% and 0% of patients treated with ertugliflozin and placebo, respectively (see section 4.4).

In the same pool, male genital mycotic infections (e.g., balanitis candida, balanoposthitis, genital infection, genital infection fungal) occurred in 3.7%, 4.2%, and 0.4% of males treated with ertugliflozin 5 mg, ertugliflozin 15 mg, and placebo, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males. In males, discontinuations due to genital mycotic infections occurred in 0.2% and 0% of patients treated with ertugliflozin and placebo, respectively. In rare instances, phimosis was reported and sometimes circumcision was performed (see section 4.4).

Urinary tract infections (ertugliflozin)
In VERTIS CV, urinary tract infections occurred in 12.2%, 12.0% and 10.2% of patients treated with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively. The incidences of serious urinary tract infections were 0.9%, 0.4%, and 0.8% with ertugliflozin 5 mg, ertugliflozin 15 mg and placebo, respectively.

Across 7 other Phase 3 clinical trials in the ertugliflozin development program, the incidences of urinary tract infections were 4.0% and 4.1% for ertugliflozin 5 mg and 15 mg groups and 3.9% for placebo. Most of the events were mild or moderate, and no serious cases were reported.


Sitagliptin
In addition to the adverse reactions described in the table above, adverse experiences reported regardless of causal relationship to medication and occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis.
Additional adverse experiences reported regardless of causal relationship to medication that occurred more frequently in patients treated with sitagliptin (not reaching the 5% level, but occurring with an incidence of > 0.5% higher with sitagliptin than that in the control group) included osteoarthritis and pain in extremity.

Some adverse reactions were observed more frequently in studies of combination use of sitagliptin with other anti-diabetic medicinal products than in studies of sitagliptin monotherapy. These included hypoglycaemia (frequency very common with the combination of sulphonylurea and metformin), influenza (common with insulin (with or without metformin)), nausea and vomiting (common with metformin), flatulence (common with metformin or pioglitazone), constipation (common with the combination of sulphonylurea and metformin), peripheral oedema (common with pioglitazone or the combination of pioglitazone and metformin), somnolence and diarrhoea (uncommon with metformin), and dry mouth (uncommon with insulin (with or without metformin)).

TECOS (trial evaluating cardiovascular outcomes with sitagliptin)
The cardiovascular safety study with sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥ 30 and < 50 mL/min/1.73 m2), and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.

In the intention-to-treat population, among patients who were using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulphonylurea at baseline, the incidence of severe hypoglycaemia was 1.0% in sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients.

Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of sitagliptin as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Mouth ulceration; stomatitis; rhabdomyolysis; tubulointerstitial nephritis.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to the Ministry of Health according to the National Regulation by using an online form
/https://sideeffects.health.gov.il